DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Preliminary Amendment
The preliminary amendment dated 11/10/2025 has been entered. Claims 5, 24, 26, 28, 29, 34, 35, 39, 43, 47, 49-52, and 56-61 are pending.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest possible effective filing date for the instant claims is June 5, 2020 based on the filing date of PCT/CN2020/094628
Election/Restriction
Applicant’s election with traverse of Group II in the reply filed on 11/10//2025 is acknowledged.
Claims 28, 29, 34, 35, 39, 43, 47, 49-52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention.
Claims 5, 24, 26 and 56-61 are under examination.
Applicant’s species election in the reply filed on 11/10/2025 is acknowledged. Applicant elected: - SEQ ID NO: 143, SEQ ID NO: 144, and SEQ ID NO: 145;
- SEQ ID NO: 146, SEQ ID NO: 147, and SEQ ID NO: 148; and
- mouse.
The traversal filed by the Applicant is on the grounds that the present claims are unified for at least the following reasons: Groups II, IV, V, and VI are closely related and searching these groups does not substantially increase the search burden.
Applicant’s arguments have been fully considered but are not found persuasive as such arguments do not apply when restriction is required under 35 USC 121 and 372, as in the instantly filed application. Thus, when the Office considers international applications as an International Searching Authority, as an International Preliminary Examining Authority, and during the national stage as a Designated or Elected Office under 35 U.S.C. 371, only PCT Rule 13.1 and 13.2 will be followed when considering unity of invention of claims of different categories without regard to the practice in national applications filed under 35 U.S.C. 111. The arguments do not contest the teaching of the reference(s) cited to establish a lack of unity.
The requirement is still deemed proper and is therefore made FINAL.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
i) the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference of the material consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (Figure 6F, 6G, 13, 14, 15 and 16A) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 5, 24, 26, and 56-61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 5, 24, 26, and 56-61 are drawn to a TCR or antigen-binding fragment thereof, comprising an alpha chain comprising a variable alpha (Va) region, wherein the Va region comprises a complementarity determining region (CDR) 1 (CDR-1), a CDR-2, and a CDR-3, wherein the Va CDR1 region comprises a sequence that is at least 80% identical to a selected Va CDR1 sequence, the Va CDR2 region comprises a sequence that is at least 80% identical to a selected Va CDR2 a sequence, the Va CDR3 region comprises a sequence that is at least 80% identical to a selected Va CDR3 sequence; and a beta chain comprising a variable beta (Vb) region, wherein the Vb region comprises a CDR-1, a CDR-2, and a CDR-3, wherein the Vb CDR1 region comprises a sequence that is at least 80% identical to a selected Vb CDR1 sequence, the Vb CDR2 region comprises a sequence that is at least 80% identical to a selected Vb CDR2 sequence, the Vb CDR3 region comprises a sequence that is at least 80% identical to a selected Vb CDR3 sequence; wherein the elected Va CDRs 1, 2, and 3 and Vb CDRs 1, 2, and 3 amino acid sequences are the elected Va CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 143, 144, and 145, respectively, and the elected Vb CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 146, 147, and 148, respectively, wherein the alpha chain comprises a mouse alpha chain constant region, and the beta chain comprises a mouse beta chain constant region. The TCR or antigen-binding fragment thereof, when expressed on the surface of a T cell, stimulates cytotoxic activity against a target cancer cell. Va region is encoded by a sequence from rearrangement of a human TRAV gene segment and a human TRAJ gene segment, and the Vb region is encoded by a sequence from rearrangement of a human TRBV gene segment and a human TRBJ gene segment, wherein the TRAV gene segment is TRAV21; the TRAJ gene segment is TRAJ33;the TRBV gene segment is TRBV10-2; and the TRBJ gene segment is TRBJ2-7. The TCR or antigen-binding fragment thereof binds to or recognizes a peptide epitope of LMP2 that is presented by a major histocompatibility complex (MHC) molecule, wherein the peptide epitope comprises an amino acid sequence of SEQ ID NO: 167 or 168. The MHC molecule is an HLA-A2 molecule. The Va region comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 200, and the Vb region comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 201.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Therefore, the claims are drawn to a genus of “TCR or antigen-binding fragment thereof“ for which there is inadequate written description.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus MPEP 2163(II)(3)(a)(i)(C).
In the instant case, the only identifying characteristic present in the claim is a recitation of requisite activity ------------------“able to bind LMP2 presented by an MHC molecule “. There is not even identification of any particular portion of a structure that must be conserved for said activity. Regarding the genus of the claims the specification describes about 14 species within the genus claimed (page 3 Lines 18 to page 4 line 30). From the specification, it is clear that Applicant is in possession of species of these 14 TCRs. The claims, however are not limited to those species but also includes any TCR with 80% identity to the corresponding CDRs and the number of such TCRs could be in the thousands. The specification fails to provide a representative number of species within the recited genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, or representative number of species, the specification does not provide adequate written description of the claimed genus.
2. Claims 5, 24, 26, and 56-61 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a T cell receptor (TCR) comprising of: (i) the elected Va CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 143, 144, and 145 respectively, and (ii) the elected Vb CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 146, 147, and 148, respectively, does not reasonably provide enablement for a TCR or antigen-binding fragment thereof, comprising an alpha chain comprising a variable alpha (Va) region, wherein the Va CDR1 region comprises a sequence that is at least 80% identical to a selected Va CDR1 sequence, the Va CDR2 region comprises a sequence that is at least 80% identical to a selected Va CDR2 sequence, the Va CDR3 region comprises a sequence that is at least 80% identical to a selected Va CDR3 sequence; and a beta chain comprising a variable beta (Vb) region, wherein the Vb CDR1 region comprises a sequence that is at least 80% identical to a selected Vb CDR1 sequence, the Vb CDR2 region comprises a sequence that is at least 80% identical to a selected Vb CDR2 sequence, the Vb CDR3 region comprises a sequence that is at least 80% identical to a selected Vb CDR3 sequence. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The specification discloses the method for constructing and sequencing of the TCR comprising of: (i) Va CDRs SEQ ID NOs: 143, 144, and 145 and (ii) Vb CDRs SEQ ID NOs: 146, 147, and 148, respectively (TCR L208), (Example 1 and 2). FIGS. 6F-6G show activation curves of TCR-T cells expressing the HLA-A2 typed anti- LMP2 TCR L208. FIG. 5E indicate that the HLA-A2 typed anti-LMP2 TCR L208 was strongly expressed in human T cells. FIG. 6E shows the results of TCR-T cells (PBMC T cells) expressing the L208 recombinant TCR when co-cultured overnight with mutant peptide SLGGLLTMV (SEQ ID NO: 168) pulsed APCs. The specification does not disclose which amino acids within the 6 CDRs sequences can be substituted and still retain the binding efficacy to peptide epitope (SEQ ID NO: 167 or 168) of LMP2 that is presented by an MHC molecule.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The art recognizes that, in general, alpha and beta chains comprising six distinct CDR sequences are required to create the TCR peptide-MHC binding site (Janeway et al., Immunobiology, 5th Ed., Garland Science, pages 106-108, 117-118 and 260-263, (2001)). In particular, the art teaches there is a bias where the TCR CDR3s are predominately involved in peptide binding, and the TCR CDR1 and CDR2 regions are predominately involved in MHC binding, although it should be noted that this bias is not absolute (Janeway et al., pages 118 and 263; Manning et al., Immunity, 1998, 8:413-425, specifically page 423, see conclusions). Further, the prior art provides the skilled artisan with insufficient guidance or direction as to which particular amino acid residues in a given CDR are required for MHC or peptide binding, or which CDR residues are required to bring about the canonical diagonal interaction of the TCR with peptide-bound MHC, see, e.g., Garcia et al., Cell, 2005, 122: 333-336, specially page 333, right column, paragraphs 1-3; page 336, col. bridging paragraph through right column, paragraph 1 and Figure 1. Indeed, one hypothesis in the art is that the CDR1 and 2 interactions with the MHC are dependent on the CDR3 interaction with the peptide bound to the MHC, and, if so, "there may be as many TCR/pMHC orientations as CDR3 sequences” (Garcia et al., page 336, column bridging paragraph). Miles et al (Immunol Cell Biol, 93:433-441, 2015) disclose that many functional, biophysical and structural studies have demonstrated that minor alterations at the TCR/pMHC interface can have huge biological ramifications and that seemingly unnoticeable changes in structure can turn a highly immunogenic antigen inert and vice versa (page 434, 2nd paragraph). However, the present claims 5, 24, 26, and 56-61 do not list the required six CDRs or the common structural features of the 6 CDR sequences that are required to create the required TCR peptide-MHC binding site but instead recite multiple variations that are at least 80% identical to the listed CDRs.
The claims are directed to a broad class antigen binding proteins only defined by its function “able to bind LMP2 presented by an MHC molecule”, with a partial structure at best. However, the specification did not give the skilled in the art enough information to choose candidate antigen binding structures from the vast number of options of millions of candidates, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification only discloses one functional TCR, L208 with specific CDRs: (i) a Va with: CDR1 (SEQ ID NO: 143), CDR2 (SEQ ID NO: 144) and a CDR3 (SEQ ID NO: 145), and (ii) a Vb with CDR1 (SEQ ID NO: 146), CDR2 (SEQ ID NO: 147) and a CDR3 (SEQ ID NO: 148), with the function of “able to bind LMP2 presented by an MHC molecule”.
Although the Supreme Court ruling in Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023) covers monoclonal antibodies, the principles are also applicable to TCRs since both monoclonal antibodies and TCRs share a similar overall structure, with both containing variable regions (including CDRs) that form an antigen-binding site and a similar protein architecture. They are both generated through gene rearrangement that creates a vast repertoire of unique receptors, and antigen specificity is determined by their CDRs.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
The instant claims are directed to a class of antigen binding molecules that include “a ‘vast’ number of additional antigen binding structures, in which the instant specification fails to describe the amino acid sequences of. It would be necessary to first generate and then screen each candidate and fragments thereof, with the recited function) to determine whether it met the functional limitations of “able to bind LMP2 presented by an MHC molecule”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant specification does not disclose any common structural feature delineating which TCRs, will have the function of “able to bind LMP2 presented by an MHC molecule”, or how to distinguish structures with this function from structures without. The only structure-function relationship guidance the specification provides is to disclose L208 with specific CDRs: (i) a Va with: CDR1 (SEQ ID NO: 143), CDR2 (SEQ ID NO: 144) and a CDR3 (SEQ ID NO: 145), and (ii) a Vb with CDR1 (SEQ ID NO: 146), CDR2 (SEQ ID NO: 147) and a CDR3 (SEQ ID NO: 148), with the function of “able to bind LMP2 presented by an MHC molecule”.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antigen binding CDRs they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
Additionally, in its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be "materially indistinguishable from those in Amgen." Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers "millions of potential candidate antibodies" (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, "the '590 patent's roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose." (Id.) Missing from the specification, according to the Federal Circuit, was "'a quality common to every functional embodiment' ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions" (id.; quoting Amgen Inc. v. Sanofi., 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta's argument that its disclosed hybridoma-and screening process "predictably and reliably generates new claimed antibodies every time it is performed" (id.), because "it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions." (Id.).
The specification does not reasonably provide enablement to use the invention of claims 5, 24, 26, and 56-61 as they are currently written. The specification does reasonably provide enablement to make and use the invention discussed supra.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary, the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
3. Claims 5, 24, 26, 56, 58, 59, and 61 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lorenz (US2022/0267407 A1 priority date August, 30, 2019).
Lorenz teaches TCR06, a TCR specific for LMP2A epitope (Fig. 14A, [0108] (instant claim 58), binding to the same epitope sequences SEQ ID NO: 167 (see alignments below). The constant region may be a human constant region, a murine constant region or a chimeric constant [0076] (instant claims 24 and 61). TCR06 has CDRs with 100% identity to the instant application TCR Va CDR sequences SEQ ID NO: 143, SEQ ID NO: 144, and SEQ ID NO: 145; and Vb CDR sequences SEQ ID NO: 146, SEQ ID NO: 147, and SEQ ID NO: 148. See below for alignments.
SEQUENCE ALIGMENTS FOR THE LMP2A epitope
Title: US-18-007-662-167
Sequence: 1 CLGGLLTMV 9
US-17-638-985-192
Sequence 192, US/17638985
Publication No. US20220267407A1
GENERAL INFORMATION
APPLICANT: Max-Delbrueck-Centrum fuer Molekulare Medizin
TITLE OF INVENTION: TCR constructs specific for EBV-derived antigens
FILE REFERENCE: 12011 P 6581WO
CURRENT APPLICATION NUMBER: US/17/638,985
CURRENT FILING DATE: 2022-02-28
NUMBER OF SEQ ID NOS: 199
SEQ ID NO 192
LENGTH: 10
Query Match 100.0%; Score 47; Length 10;
Best Local Similarity 100.0%;
Matches 9; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CLGGLLTMV 9
|||||||||
Db 2 CLGGLLTMV 10
SEQUENCE ALIGMENTS FOR THE VA CDRs
Title: US18007662_143FUS144FUS145
US-17-638-985-15
Sequence 15, US/17638985
Sequence: 1 DSAIYNIQSSQRECAVLMDSNYQLIW 26
Publication No. US20220267407A1
GENERAL INFORMATION
APPLICANT: Max-Delbrueck-Centrum fuer Molekulare Medizin
TITLE OF INVENTION: TCR constructs specific for EBV-derived antigens
CURRENT APPLICATION NUMBER: US/17/638,985
CURRENT FILING DATE: 2022-02-28
NUMBER OF SEQ ID NOS: 199
SEQ ID NO 15
LENGTH: 113
FEATURE:
OTHER INFORMATION: TCR06 - TRA - variable region
Query Match 81.6%; Score 111; Length 113;
Best Local Similarity 34.2%;
Matches 26; Conservative 0; Mismatches 0; Indels 50; Gaps 2;
Qy 1 DSAIYN-----------------IQSSQRE------------------------------ 13
|||||| |||||||
Db 27 DSAIYNLQWFRQDPGKGLTSLLLIQSSQREQTSGRLNASLDKSSGRSTLYIAASQPGDSA 86
Qy 14 ---CAVLMDSNYQLIW 26
|||||||||||||
Db 87 TYLCAVLMDSNYQLIW 102
SEQUENCE ALIGMENTS FOR THE VA CDRs
Title: US-18-007-662-146FUS147FUS148
Sequence: 1 WSHSYSAAADICASSEDGMNTEAFF 25
US-17-638-985-20
Sequence 20, US/17638985
Publication No. US20220267407A1
GENERAL INFORMATION
APPLICANT: Max-Delbrueck-Centrum fuer Molekulare Medizin
TITLE OF INVENTION: TCR constructs specific for EBV-derived antigens
FILE REFERENCE: 12011 P 6581WO
CURRENT APPLICATION NUMBER: US/17/638,985
CURRENT FILING DATE: 2022-02-28
NUMBER OF SEQ ID NOS: 199
SEQ ID NO 20
LENGTH: 113
FEATURE:
OTHER INFORMATION: TCR06 - TRB - variable region
Query Match 81.3%; Score 109.7; Length 113;
Best Local Similarity 32.1%;
Matches 25; Conservative 0; Mismatches 0; Indels 53; Gaps 2;
Qy 1 WSHS-----------------YSAAADI-------------------------------- 11
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Db 27 WSHSYMFWYRQDLGHGLRLIYYSAAADITDKGEVPDGYVVSRSKTENFPLTLESATRSQT 86
Qy 12 ----CASSEDGMNTEAFF 25
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Db 87 SVYFCASSEDGMNTEAFF 104
Lorenz discloses a pharmaceutical composition for the treatment of a cancer or infectious agent from which the epitopes targeted by the TCR constructs are derived [0106]. The infection or cancer may be associated, e.g., with EBV. In this case, the different EBV antigens may be LMP2A [0107] which reads on the TCR, when expressed on a T cell, stimulates cytotoxic activity against a target cancer cell (instant claim 26). While Lorenz does not explicitly disclose all the properties of their TCR06 CDRs (such as epitope binding, epitope presented by an HLA-A2 (instant claims 58 and 59), etc.), these properties would inherently be the same properties and functions than the TCR CDRs of the instant application since the CDRs disclosed by Lorenz are the same CDRs recited in instant claims 5 and 56. "Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01".
Therefore, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary.
Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
4. Claims 5, 24, 26 and 56-61 are rejected under 35 U.S.C. 103 as being unpatentable over Lorenz in view of Goldfless (US 2019/0321401 A1 publication date October 24, 2019), A0A0B4J279.1 (Nature 421 (6923), 601-607 (2003), GenPept http://ncbi.nlm.nih.gov/protein/A0A0B4J279.1?report=genbank&log$=protalign&blast_rank=1&RID=K0XR6XY8014) and A0A0K0K1A3.3 (Nature 424 (6945), 157-164 (2003) GenPept https://www.ncbi.nlm.nih.gov/protein/A0A0K0K1A3.3?report=genbank&log$=protalign&blast_rank=1&RID=K0Y35VM4014)
Lorenz teachings have been discussed above and incorporated herein. In addition, the amino acids 1-113 of TCR06 (SEQ ID NO: 15) is 100% identical to the amino acids 20-131 Va region of L208 ( (see sequence SEQ ID NO: 200) and the amino acids 1-114 of TCR06 (SEQ ID NO: 20) is 100% identical to the amino acids 20-132 Va region of L208 ( (see sequence SEQ ID NO: 201), (see alignments below). Lorenz teaches that TCR06 has the TRAV21 and TRB10-2 gene segments (page 14, table 4) but since the sequences are 100% identical as shown below, the TRAJ gene sequence is TRAJ33 and the TRBJ gene segment must be TRJ2-7 as required by instant claim 57.
Lorenz does not teach the presence of amino acids 1-19 of SEQ ID NOs: 200 and 201 in TCR06 Va or Vb regions of L208 as required by instant claim 57
Goldfless teaches the existence of signal sequences (SEQ ID NO: 328 METLLGLLILWLQLQWVSS being one of them,) also called signal peptides or leader sequences [0174] that are not part of the variable or constant regions of the TCR [0180]. This reads on the precursor TCR has a leader sequence that is present in the mRNA. This leader sequence encodes a signal peptide, that directs the protein to the cell surface. The signal peptide is then cleaved off during the maturation process, leaving a functional TCR protein. Therefore, these signal peptides do not change the structure of the variable regions or TCR binding.
Goldfless does not teach the signal sequence MGTRLFFYVALCLLWAGHR.
A0A0B4J279.1 teaches the signal peptide METLLGLLILWLQLQWVSS (see sequences alignments below) as required by instant claim 57
A0A0K0K1A3.3 teaches the signal peptide MGTRLFFYVALCLLWAGHR (see sequences alignments below) as required by instant claim 57.
SEQUENCE ALIGMENTS FOR THE TCR (Va region SEQ ID NO: 200) comprising amino acid 1-19 from A0A0B4J279.1 and 20-113 from Lorenz with a combined 100% identity.
Title: US-18-007-662-200
Sequence: 1 METLLGLLILWLQLQWVSSK..........LMDSNYQLIWGAGTKLIIKP 131
Database : US-17-638-985-15.pep:*
SUMMARIES
Result Query
No. Score Match % Length DB ID Description
----------------------------------------------------------------------------
1 569 85.4 113 1 US-17-638-985-15 TCR constructs
ALIGNMENTS
US-17-638-985-15
Query Match 85.4%; Score 569; DB 1; Length 113;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 20 KQEVTQIPAALSVPEGENLVLNCSFTDSAIYNLQWFRQDPGKGLTSLLLIQSSQREQTSG 79
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Db 1 KQEVTQIPAALSVPEGENLVLNCSFTDSAIYNLQWFRQDPGKGLTSLLLIQSSQREQTSG 60
Qy 80 RLNASLDKSSGRSTLYIAASQPGDSATYLCAVLMDSNYQLIWGAGTKLIIKP 131
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Db 61 RLNASLDKSSGRSTLYIAASQPGDSATYLCAVLMDSNYQLIWGAGTKLIIKP 112
Amino acids 1-19 from SEQ ID NO: 200: METLLGLLILWLQLQWVSS
RecName: Full=T cell receptor alpha variable 21; Flags: Precursor
UniProtKB/Swiss-Prot: A0A0B4J279.1
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98
458
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111
888
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SEQUENCE ALIGMENTS FOR THE TCR (Vb region SEQ ID NO: 201) comprising amino acid 1-19 from A0A0K0K1A3.3 and 20-113 from Lorenz, with a combined 100% identity.
Title: US-18-007-662-201
Sequence: 1 MGTRLFFYVALCLLWAGHRD..........SEDGMNTEAFFGQGTRLTVV 132
Database : US-17-638-985-20.pep:*
SUMMARIES
Result Query
No. Score Match % Length DB ID Description
----------------------------------------------------------------------------
1 600 84.9 113 1 US-17-638-985-20 TCR constructs
ALIGNMENTS
US-17-638-985-20
Query Match 84.9%; Score 600; DB 1; Length 113;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 20 DAGITQSPRYKITETGRQVTLMCHQTWSHSYMFWYRQDLGHGLRLIYYSAAADITDKGEV 79
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Db 1 DAGITQSPRYKITETGRQVTLMCHQTWSHSYMFWYRQDLGHGLRLIYYSAAADITDKGEV 60
Qy 80 PDGYVVSRSKTENFPLTLESATRSQTSVYFCASSEDGMNTEAFFGQGTRLTVV 132
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PDGYVVSRSKTENFPLTLESATRSQTSVYFCASSEDGMNTEAFFGQGTRLTVV 113
Amino acids 1-19 from SEQ ID NO: 201: MGTRLFFYVALCLLWAGHR
RecName: Full=T cell receptor beta variable 10-1; Flags: Precursor
UniProtKB/Swiss-Prot: A0A0K0K1A3.3
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101
461
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121
902
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It would have been obvious to one of ordinary skill in the art to combine the teachings of Lorenz, Goldfless and A0A0B4J279.1 to generate a protein comprising the signal peptide of Goldfless and A0A0B4J279.1 and the TCR Va of Lorenz. It would have been obvious to one of ordinary skill in the art to combine the teachings of Lorenz and A0A0K0K1A3.3 to generate a protein comprising the signal peptide of A0A0K0K1A3.3 and the TCR Vb of Lorenz. One of ordinary skill would have been motivated to do so because the signal peptides help directing the TCR Va and Vb taught by Lorenz to the cell surface without affecting the TCR structure since the signal peptide is cleaved. It would further be obvious that the combinations described above would be 100% identical to SEQ ID NOs: 200 and 201 and thus comprise TRAV21, TRAJ33, TRBV10-2; and TRBJ2-7. There would be a reasonable expectation of success because combining these sequences can be done with standard cloning techniques.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671